Nitric oxide (NO) is an important physiological regulator of vascular function. Recent data indicate that NO also has a significant role in the modulation of tissue oxygen consumption. The roles of NO in skeletal muscle hyperemia and oxygen consumption in humans are unclear. There are no definitive data regarding whether NO production increases in skeletal muscle during exercise. Whether NO contributes to the regulation of skeletal muscle oxygen uptake at rest and during exercise in humans is also unclear. The proposed experiments will test 1) whether NO production in skeletal muscle increases during dynamic exercise; 2) whether NO produced during exercise in skeletal muscle contributes to the hyperemia associated with exercise; and 3) whether endogenous NO modulates skeletal muscle oxygen consumption at rest and during exercise. We will measure the conversion of arginine to citrulline, using stable isotope techniques, as a direct index of endothelial NO production; we will also use blockade of NO synthesis via infusion of L-NMMA. Exercising muscle oxygen consumption (VO2) will be measured directly and whole body VO2 will be measured at the mouth. The strength of the proposed experimental design is that we will study basic mechanisms of circulatory control during exercise in humans. The results of these experiments will provide important new information about the mechanistic role of NO in the regulation of skeletal muscle blood flow and oxygen consumption in humans.